Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.

"Heterogeneity" in tumor mass has immense importance in cancer progression and therapy. The impact of tumor heterogeneity is an emerging field and not yet fully explored. Tumor heterogeneity is mainly considered as intra-tumor heterogeneity and inter-tumor heterogeneity based on their origin. Intra-tumor heterogeneity refers to the discrepancy within the same cancer mass while inter-tumor heterogeneity refers to the discrepancy between different patients having the same tumor type. Both of these heterogeneity types lead to variation in the histopathological as well as clinical properties of the cancer mass which drives disease resistance towards therapeutic approaches. Cancer stem cells (CSCs) act as pinnacle progenitors for heterogeneity development along with various other genetic and epigenetic parameters that are regulating this process. In recent times epigenetic factors are one of the most studied parameters that drive oxidative stress pathways essential during cancer progression. These epigenetic changes are modulated by various epidrugs and have an impact on tumor heterogeneity. The present review summarizes various aspects of epigenetic regulation in the tumor microenvironment, oxidative stress, and progression towards tumor heterogeneity that creates complications during cancer treatment. This review also explores the possible role of epidrugs in regulating tumor heterogeneity and personalized therapy against drug resistance.

A Computational Insight on the Inhibitory Potential of 8-Hydroxydihydrosanguinarine (8-HDS), a Pyridone Containing Analog of Sanguinarine, against SARS CoV2.

The unprecedented global pandemic of COVID-19 has created a daunting scenario urging an immediate generation of therapeutic strategy. Interventions to curb the spread of viral infection primarily include setting targets against the virus. Here in this study we target S protein to obstruct the viral attachment and entry and also the M pro to prevent the viral replication. For this purpose, the interaction of S protein and M pro with phytocompounds, sanguinarine and eugenol, and their derivatives were studied using computational tools. Docking studies gave evidence that 8-hydroxydihydrosanguinarine (8-HDS), a derivative of sanguinarine, showed maximum binding affinity with both the targets. The binding energies of the ligand with S protein and M pro scored to be ΔGb -9.4 Kcal/mol and ΔGb -10.3 Kcal/mol, respectively. MD simulation studies depict that the phytocompound could effectively cause structural perturbations in the targets which would affect their functions. 8-Hydroxydihydrosanguinarine distorts the α-helix in the secondary structure of M pro and RBD site of S protein. Protein-protein interaction study in presence of 8-hydroxydihydrosanguinarine also corroborate the above findings which indicate that this polyphenol interferes in the coupling of S protein and ACE2. The alterations in protonation of M pro suggest that the protein structure undergoes significant structural changes at neutral pH. ADME property of 8-hydroxydihydrosanguinarine indicates this could be a potential drug. This makes the phyto-alkaloid a possible therapeutic molecule for anti COVID-19 drug design.

Therapeutic Potential and Ethnopharmacology of Dominant Mangroves of Bhitarkanika National Park, Odisha, India.

Bhitarkanika National Park is the second largest contiguous mangrove forest of India. Approximately 0.15 million mangrove depending population are found residing in and around 307 villages within the National Park. Despite being one of the most diverse mangrove habitations of India, the ethnopharmacological practices are meager in comparison to the other mangrove regions of India and Southeast Asia. The present review is aimed to congregate information on the therapeutic potential and ethnopharmacology of nine dominant mangrove species of the National Park, such as Aegiceras corniculatum, Avicenia marina, Avicenia officinalis, Ceriops decandra, Excoecaria agallocha, Heritiera fomes, Lumnitzera racemosa, Rhizophora mucronata, and Sonneratia apetala. Our aim is to generate social awareness among the mangrove dwellers to promote uses of folklore medicine using these tremendously potential mangrove plants, as a complementary step to strengthen community health. Further, we also want to grab the attention of researchers working in related disciplines, for their holistic and extensive studies towards bio-prospectation of the dominant mangrove plants of Bhitarkanika National Park.

A primer on cytokines.

Cytokines are pleiotropic polypeptides that control the development of and responses mediated by immune cells. Cytokine classification predominantly relies on [1] the target receptor(s), [2] the primary structural features of the extracellular domains of their receptors, and [3] their receptor composition. Functionally, cytokines are either pro-inflammatory or anti-inflammatory, hematopoietic colony-stimulating factors, developmental and would healing maintaining immune homeostasis. When the balance in C can form complex networks amongst themselves that may affect the homeostasis and diseases. Cytokines can affect resistance and susceptibility for many diseases and their availability in the host cytokine production and interaction is disturbed, immunopathogenesis sets in. Therefore, cytokine-targeting bispecific, and chimeric antibodies form a significant mode of immnuo-therapeutics Although the field has grown deep and wide, many areas of cytokine biology remain unknown. Here, we have reviewed these cytokines along with the organization, signaling, and functions through respective cytokine-receptor-families. Being part of the special issue on the Role of Cytokines in Leishmaniasis, this review is intended to be used as an organized primer on cytokines and not a resource for detailed discussion- for which a two-volume Handbook of cytokines is available- on each of the cytokines. Priming the readers on cytokines, we next brief the role of cytokines in Leishmaniasis. In the brief, we do not provide an account of each of the involved cytokines known to date, instead, we offer a temporal relationship between the cytokines and the progress of the infection towards the alternate outcomes- healing or non-healing- of the infection.

Pro-inflammatory cytokine Interleukin-1ß (IL-1ß) controls Leishmania infection.

Leishmania is an obligate intracellular parasite uses low pH phagolysosomal compartments of host macrophages as their final abode. IL-1ß is a pro inflammatory cytokine, which is secreted by immune cells to trigger inflammation and this has been found profoundly in the lesions caused by Leishmania pathogens. But the specific role of this cytokine on host cell macrophages during infection has not been fully explored. Here in, we have showed that prolonged exposure of IL-1ß on macrophages increases the parasite burden. Pre-treatment of bone marrow derived macrophages (BMDM) with IL-1ß also generates significantly higher amount of anti-inflammatory cytokine IL-10. As IL-10 plays crucial role in the establishment of infection, enhanced production of IL-10 observed upon IL-1ß treatment could contribute to the progression of the disease. By quantifying the production of Nitric oxide (NO), we further report that the pretreatment of IL-1ß fails to produce the nitric oxide. By measuring the footpad thickness in two different mice strains of differential susceptibility we showed IL-1ß treatment increases parasitic burden. As our results shows that the exposure of IL-1ß helps in disease progression, IL-1ß signalling may be an attractive target for future therapeutic intervention.

Neonatal Persistent Exposure to 6-Propyl-2-thiouracil, a Thyroid-Disrupting Chemical, Differentially Modulates Expression of Hepatic Catalase and C/EBP-ß in Adult Rats.

Persistent exposure of rats to 6-propyl-2-thiouracil (PTU) from birth resulted in decreases in plasma thyroid hormone (TH) levels and hepatic expression of catalase and CCAAT enhancer binding protein ß (C/EBP-ß). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-ß showed an augmentation in the methylation level along with a change in methylation pattern of CpG islands in response to PTU treatment. PTU withdrawal on 30 days of birth restored TH levels and C/EBP-ß to control rats in adulthood. Although catalase expression was restored to some extent in adult rats in response to PTU withdrawal, a permanent change in its promoter CpG methylation pattern was recorded. The results suggest that downregulation of adult hepatic catalase gene in response to persistent neonatal PTU exposure may not solely be attributed to thyroid-disrupting properties of PTU. It is possible that besides thyroid-disrupting behavior, PTU may impair expression of hepatic catalase by altering methylation pattern of its promoter.

Effect of heavy metals on growth response and antioxidant defense protection in Bacillus cereus.

Bacterial cells in aerobic environment generate reactive oxygen species which may lead to oxidative stress, induced by a wide range of environmental factors including heavy metals. In the present context an attempt has been made to determine the toxic impact of cadmium and copper on growth performance, oxidative stress, and relative level of antioxidant protection in Bacillus cereus. Outcome of this study suggests that both the metal ions depleted the growth rate in this organism with respect to time and concentration of the metal ions. CdCl2 exposure induced extracellular glutathione (GSH) production, whereas, its level was declined in response to CuSO4. Superoxide dismutase (SOD) activity and hydrogen peroxide (H2 O2 ) content was elevated under CdCl2 stress but the activity of catalase (CAT) was inhibited. In contrast, incubation of bacteria with CuSO4 exhibited decreased SOD activity with concomitant rise in CAT activity and H2 O2 content. We also observed elevation of intracellular GSH level in this bacteria following supplementation of N-acetyl cysteine (NAC) in the medium. Overall findings of this study indicated differential toxicity of CdCl2 and CuSO4 in inducing oxidative stress, depleting growth rate and the possible involvement of GSH and CAT in adaptive antioxidant response.

Arsenic album 30C exhibits crystalline nano structure of arsenic trioxide and modulates innate immune markers in murine macrophage cell lines.

Macrophages are associated with innate immune response and M1-polarized macrophages exhibit pro-inflammatory functions. Nanoparticles of natural or synthetic compounds are potential triggers of innate immunity. As2O3 is the major component of the homeopathic drug, Arsenic album 30C.This has been claimed to have immune-boosting activities, however, has not been validated experimentally. Here we elucidated the underlying mechanism of Ars. alb 30C-mediated immune priming in murine macrophage cell line. Transmission Electron Microscopy (TEM) and X-ray diffraction (XRD) used for the structural analysis of the drug reveals the presence of crystalline As2O3 nanoparticles of cubic structure. Similarly, signatures of M1-macrophage polarization were observed by surface enhanced Raman scattering (SERS) in RAW 264.7 cells with concomitant over expression of M1 cell surface marker, CD80 and transcription factor, NF-κB, respectively. We also observed a significant increase in pro-inflammatory cytokines like iNOS, TNF-α, IL-6, and COX-2 expression with unaltered ROS and apoptosis in drug-treated cells. Enhanced expression of Toll-like receptors 3 and 7 were observed both in transcriptional and translational levels after the drug treatment. In sum, our findings for the first time indicated the presence of crystalline As2O3 cubic nanostructure in Ars. alb 30C which facilitates modulation of innate immunity by activating macrophage polarization.

Curcumin differentially regulates the expression of superoxide dismutase in cerebral cortex and cerebellum of L-thyroxine (T4)-induced hyperthyroid rat brain.

The present investigation was aimed to elucidate the effect of curcumin on lipid peroxidation (LPx) and superoxide dismutase (SOD) in L-thyroxine (T4)-induced oxidative stress in cerebral cortex and cerebellum of rat brain. Elevated level of LPx in cerebral cortex declined to control level on supplementation of curcumin to T4-treated rats. On the other hand, unaltered LPx level in T4-treated rats showed a significantly decreased level of LPx on supplementation of curcumin. The increased activity of SOD and translated products of SOD1 and SOD2 in cerebral cortex of T4-treated rats was ameliorated on supplementation of curcumin. The decreased activity of SOD and protein expression of SOD1 in cerebellum of T4-treated rats were ameliorated on administration of curcumin. On the other hand, SOD2 expression was not influenced either by T4-treated or by curcumin supplementation to T4-treated rats. Results of the present investigation reveal that the regulation of expression of SOD by curcumin in different regions (cerebral cortex and cerebellum) of rat brain is different under hyperthyroidism.

Thermodynamics of benzoquinone-induced conformational changes in nucleic acids and human serum albumin.

Biological macromolecules such as proteins, nucleic acids, carbohydrates and lipids, play a crucial role in biochemical and molecular processes. Thus, the study of the structure-function relationship of biomolecules in presence of ligands is an important aspect of structural biology. The current communication describes the chemico-biological interaction between benzene metabolite para-benzoquinone (BQ) with B-form of nucleic acids (B-DNA) and human serum albumin (HSA). The binding ability of HSA towards bromocresol green (BCG) was significantly suppressed when exposed to increasing concentrations of BQ in the presence of various physiological buffers. Further, the native fluorescence of HSA was drastically reduced and the secondary structures of HSA were significantly compromised with increasing concentrations of BQ. In vitro and in silico studies also revealed that BQ binds to domains I and II of HSA and thus altering the conformation of HSA which may potentially affect plasma osmotic pressure, as well as the binding and transport of numerous endogenous and exogenous molecules. Similarly, BQ interacts directly to the GC region of B-DNA particularly in the minor groove which was also assessed by computational docking studies. Isothermal titration calorimetry data suggest higher binding affinity of BQ towards DNA than HSA. Various spectroscopic observations also suggest that BQ binds to DNA preferably in the minor grooves. Thus, the results revealed that BQ may play a key role in inducing mutagenicity, either by formation of adducts on GC regions or by accelerating oxidative damage to biomacromolecules through chemico-biological interactions.

Crystal structure of the N-terminal domain of MtClpC1 in complex with the anti-mycobacterial natural peptide Lassomycin.

Antibiotics form our frontline therapy against disease-causing bacteria. Unfortunately, antibiotic resistance is becoming more common, threatening a future where these medications can no longer cure infections. Furthermore, the emergence of multidrug-resistant (MDR), totally drug-resistant (TDR), and extensively drug-resistant (XDR) tuberculosis has increased the urgency of discovering new therapeutic leads with unique modes of action. Some natural peptides derived from actinomycetes, such as Cyclomarin A, Lassomycin, Rufomycin I, and Ecumicin, have potent and specific bactericidal activity against Mycobacterium tuberculosis, with the specificity owing to the fact that these peptides target the ClpC1 ATPase, an essential enzyme in mycobacteria, and inhibit/activate the proteolytic activity of the ClpC1/P1/P2 complex that participates in protein homeostasis. Here, we report the high-resolution crystal structure of the N-terminal domain of ClpC1 (ClpC1 NTD) in complex with Lassomycin, showing the specific binding mode of Lassomycin. In addition, the work also compares the Lassomycin complex structure with the previously known structures of ClpC1 NTD in complex with other natural peptides such as Cyclomarin A, Rufomycin I, and Ecumicin.

Expression of antioxidant genes in renal cortex of PTU-induced hypothyroid rats: effect of vitamin E and curcumin.

The present study was undertaken to investigate the effect of vitamin E and curcumin on the expression of antioxidant genes in 6-propyl-2-thiouracil (PTU)-induced hypothyroid rat renal cortex. The levels of lipid peroxidation and protein carbonylation were increased in hypothyroid rat kidney. Co-administration of vitamin E and curcumin to hypothyroid rats resulted in amelioration of lipid peroxidation level, whereas curcumin alone alleviated the protein carbonylation level. The mRNA levels of SOD1 and SOD2 were decreased in hypothyroid rats. Decreased level of SOD1 transcripts was observed in hypothyroid rats supplemented with curcumin alone or co-administrated with vitamin E. Translated products of SOD1 and SOD2 in hypothyroid rats was elevated in response to supplementation of both the antioxidants. Decreased SOD1 and SOD2 activities in hypothyroid rats compared to control were either unaltered or further decreased in response to the antioxidants. Expressions of CAT at transcript and translate level along with its activity were down regulated in hypothyroid rats. Administration of vitamin E to hypothyroid rats resulted in elevated CAT mRNA level. In contrast, expression of CAT protein was elevated in response to both the antioxidants. However, CAT activity was unaltered in response to vitamin E and curcumin. GPx1 and GR mRNA level and the activity of glutathione peroxidase (GPx) were not affected in response to induced hypothyroidism. The activity of GPx was increased in response to vitamin E treatment, whereas decreased GR activity in hypothyroid rats was further declined by the administration of antioxidants. The over all results suggest that vitamin E and curcumin differentially modulate the altered antioxidant defence mechanism of rat kidney cortex under experimental hypothyroidism.

Hypothyroidism modulates renal antioxidant gene expression during postnatal development and maturation in rat.

In the present study effects of 6-n-propyl thiouracil (PTU)-induced hypothyroidism on renal antioxidant defence system during postnatal development (from birth to 7, 15 and 30days old) and on adult rats were reported. Hypothyroidism in rats was induced by feeding the lactating mothers (from the day of parturition till weaning, 25days old) or directly to the pups with 0.05% PTU in drinking water. The activities of Cu/Zn-superoxide dismutase (SOD1) and glutathione peroxidase (GPx) were increased in 30days old hypothyroid rats with respect to their respective controls, on the other hand, levels of translated products and activities of Mn-superoxide dismutase (SOD2) and catalase (CAT) were decreased in hypothyroid rats of all age groups as compared to their respective control rats. SOD1 activity remained unchanged in persistent (PTU-treatment from birth to 90days old) hypothyroid rats as compared to euthyroid. However, a decreased activity of SOD1 was recorded in transient (PTU-treatment from birth to 30days then withdrawal till 90days old) hypothyroid rats with respect to control rats. The mRNA level, protein expression and activity of SOD2 and CAT were significantly decreased in persistent hypothyroid rats as compared to euthyroid rats. The activity of GPx was significantly increased in both persistent and transient hypothyroid rats with respect to euthyroid rats. The present study indicates modulation of antioxidant defence status of rat kidney during postnatal development and maturation by hypothyroidism.

Induction of oxidative stress and inhibition of superoxide dismutase expression in rat cerebral cortex and cerebellum by PTU-induced hypothyroidism and its reversal by curcumin.

The present study was carried out to elucidate the effectiveness of curcumin in ameliorating the expression of superoxide dismutase (SOD) in cerebral cortex and cerebellum of rat brain under 6-propyl-2-thiouracil (PTU)-induced hypothyroidism. Induction of hypothyroidism in adult rats by PTU resulted in augmentation of lipid peroxidation (LPx), an index of oxidative stress in cerebellum but not in cerebral cortex. Curcumin-supplementation to PTU-treated (hypothyroid) rats showed significant reduction in the level of LPx in both the regions of brain. The decreased translated products (SOD1 and SOD2) and the unchanged activity of SOD in cerebral cortex of PTU-treated rats were increased on supplementation of curcumin to the hypothyroid rats. Declined translated products of SOD1 and SOD2 in cerebellum of PTU-treated rats were alleviated on administration of curcumin to hypothyroid rats. On the other hand, the decreased activity of SOD in cerebellum of PTU-treated rats was further declined on administration of curcumin to the hypothyroid rats. Results of the present investigation indicate that curcumin differentially modulates the expression of superoxide dismutase in rat brain cortex and cerebellum under PTU-induced hypothyroidism.

CTK7A, a curcumin derivative, can be a potential candidate for targeting HIF-1α/p300 complex: Evidences from in vitro and computational studies.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor which plays a critical role in several biochemical pathways, and consists of oxygen-dependent alpha (α) and a constitutively expressed beta (ß) subunit. Under hypoxic conditions, HIF-1α is stabilized and forms a complex with ß subunit and this complex is associated with cancer progression. HIF-1α activity is mainly regulated by its transcriptional co-activator p300 which has histone acetyl-transferase (HAT) activity. p300 HAT activity is very crucial for p300 auto-acetylation and subsequently its interaction with its partner molecule HIF-1α as well as proapoptotic protein p53. p300 is a multi-domain protein and CH1 domain of p300 is the interacting partner of the C-terminal domain (CTD) of HIF-1α as well as p53. Several p300 HAT inhibitors are reported to suppress p300 auto-acetylation which inhibits its interaction with associated partners. We demonstrated that the p300 HAT inhibitor CTK7A down-regulated p300 auto-acetylation, HIF-1α accumulation as well as activity in gastric cancer cell lines. Protein-protein interaction and molecular docking studies revealed a significant decrease in the binding energy of full-length p300 as well as p300-CH1 and HIF-1α-CTD complex in presence of CTK7A. Further, SwissADME, evaluates the drug-likeliness property of CTK7A by analyzing its lipophilicity, size, polarity, solubility, saturation, and flexibility. Our in vitro and in silico data support reduced HIF-1α-p300 interaction in the presence of CTK7A. Hence, CTK7A might be playing a crucial role in down-regulating HIF-1α activity and can be a prospective anticancer drug.

Epigenetic signature in neural plasticity: the journey so far and journey ahead.

Neural plasticity is a remarkable characteristic of the brain which allows neurons to rewire their structure in response to internal and external stimuli. Many external stimuli collectively referred to as 'epigenetic factors' strongly influence structural and functional reorganization of the brain, thereby acting as a potential driver of neural plasticity. DNA methylation and demethylation, histone acetylation, and deacetylation are some of the frontline epigenetic mechanisms behind neural plasticity. Epigenetic signature molecules (mostly proteins) play a pivotal role in epigenetic reprogramming. Though neuro-epigenetics is an incredibly important field of emerging research, the critical role of signature proteins associated with epigenetic alteration and their involvement in neural plasticity needs further attention. This study gives an integrated and systematic overview of the current state of knowledge with a clear idea of types of neural plasticity and the context-dependent role of epigenetic signature molecules and their modulation by some natural bioactive compounds.

The modulatory role of prime identified compounds in Geophila repens in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Geophila repens (L.) I.M. Johnst (Rubiaceae) is a small perennial creeper native to India, China, and other countries in Southeast Asia. The hot decoction of leaves is used orally for memory enhancing by the local folk of Andhra Pradesh, India. The ethnomedicinal claim of G. repens as memory enhancer was initially studied by the authors. Results demonstrated the important antioxidant and anticholinesterase activities of isolated molecule Pentylcurcumene and bioactive hydroalcohol extract of leaves of G. repens (GRHA). AIM OF THE STUDY: Based on the previous findings, additional research is needed to examine the efficacy of GRHA for memory enhancing properties. We therefore investigated the modulatory role of prime identified compounds in GRHA in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease (AD) via attenuation of cholinesterase, ß-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation. METHODS: Scopolamine (3 mg/kg) induced experimental rats of AD were treated with GRHA (300, 400 mg/kg) for 14 days. During the experimental period, elevated T-maze and locomotion-activity were performed to assess learning and memory efficacy of GRHA. At the end of the experiment, biochemical, neurochemical, neuroinflammation and histopathological observation of brain cortex were examined. GC-MS/MS analysis reported 31 compounds, among them 8 bioactive compounds possess antioxidant, neuroinflammation, neuroprotective activities, and were considered for docking analysis towards cholinesterase, ß-secretase activities in AD. RESULTS: GRHA 400 significantly improved learning and memory impairment with the improvement of oxidative stress (MDA, SOD, GSH, CAT), DNA damage (8-OHdG), neurochemical (AChE, BuChE, BACE1, BACE2, MAPt), neuroinflammation (IL-6, TNF-α) markers in neurotoxic rats. Docking studies of 8 compounds demonstrated negative binding energies for cholinesterase and ß-secretase indicating high affinity for target enzymes in AD. Test results were corroborated by the improvement of cellular tissue architecture of brain cortex in AD rats. CONCLUSION: Synergistic action of genistin, quercetin-3-D-galactoside, 9,12,15-octadecatrienoic-acid methyl-ester, phytol, retinal, stigmasterol, n-hexadecanoic acid, ß-sitosterol in GRHA restores memory-deficits via attenuation of cholinesterase, ß-secretase, MAPt level and inhibition of oxidative-stress imparts inflammation in AD.

Recombinant expression, purification and SAXS analysis of Arabidopsis thaliana ClpC1.

Caseinolytic protease-associated chaperones (Clp chaperones) are HSP100 proteins belonging to the family of ATPases having diverse cellular functions, and they occur in various organisms ranging from bacteria to plants and mammals. Most Clp chaperones have a hexameric organization and associate with tetradecameric Clp proteases to recognize and unfold protein substrates that get degraded within the cellular milieu. Vascular plants have a diverse family of Clp chaperones compared to other organisms; wherein, the chloroplasts of Arabidopsis thaliana alone contain four distinct Clp chaperones, such as ClpC1, ClpC2, ClpD, and ClpB3. The paralogs AtClpC1 and AtClpC2 are more than 90% identical, though the extent of functional overlap between the two is not clear. Moreover, in vitro characterization reports are available only for AtClpC2, as AtClpC1 could not be expressed in recombinant form in the past. Herein, using a bacterial expression system, we have successfully expressed and purified AtClpC1 with a short N-terminal truncation, employing a three-step chromatographic purification strategy. We show that AtClpC1 exists as a hexamer in the presence of ATP and MgCl2, as known for other functional Clp chaperones. Further, our SAXS analyses provide a low-resolution envelope structure for the hexameric AtClpC1, which very well fits a ClpC hexamer model.

Factors regulating dynamics of angiotensin-converting enzyme-2 (ACE2), the gateway of SARS-CoV-2: Epigenetic modifications and therapeutic interventions by epidrugs.

Angiotensin-converting enzyme-2 (ACE2) is one of the major components of the renin-angiotensin system (RAS) and participates in the physiological functions of the cardiovascular system and lungs. Recent studies identified ACE2 as the receptor for the S-protein of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and thus acts as the gateway for viral entry into the human body. Virus infection causes an imbalance in the RAS axis and induces acute lungs injury and fibrosis. Various factors regulate ACE2 expression patterns as well as control its epigenetic status at both transcription and translational levels. This review is mainly focused on the impact of environmental toxicants, drugs, endocrine disruptors, and hypoxia as controlling parameters for ACE2 expression and its possible modulation by epigenetic changes which are marked by DNA methylation, histone modifications, and micro-RNAs (miRNAs) profile. Furthermore, we have emphasized on interventions of various phytochemicals and bioactive compounds as epidrugs that regulate ACE2-S-protein interaction and thereby curb viral infection. Since ACE2 is an important component of the RAAS axis and a crucial entry point of SARS-CoV-2, the dynamics of ACE2 expression in response to various extrinsic and intrinsic factors are of contemporary relevance. We have collated updated information on ACE2 expression modulated by epidrugs, and urge to take over further studies on these important physiological regulators to unravel many more systemic linkages related to both metabolic and infectious diseases, in general and SARS-CoV-2 in particular for further development of targeted interventions.

Interface-based design of the favipiravir-binding site in SARS-CoV-2 RNA-dependent RNA polymerase reveals mutations conferring resistance to chain termination.

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%-98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.